1. Field of the Invention
The present invention relates to novel N-substituted amide derivatives useful in the field of medicines, and especially for prevention and therapy for liver diseases.
2. Description of the Prior Art
The liver suffers acute or chronic injuries such as, for example, fatty liver, jaundice and hepatic cirrhosis by various reasons such as virus, alcohol, malnutrition and hepatic circulation injuries. Malutilate and the like are recently reported as a therapeutic agent for these liver diseases. However, there have not been found actually effective therapy and therapeutic agents including symptomatic therapy such as dietetic therapy, and drug therapy by administration of steroids or immunoactivators.
As stated above, there has not yet been any satisfactory therapy for liver diseases, especially delayed and chronic diseases. In addition, drug therapy by administration of steroids and immunoactivators has a problem which side-effects of the drugs are serious.
As a result of synthesis of various N-substituted amide derivatives to develop the therapeutical agents of liver diseases for solving the above problem, the present inventors have found that certain compounds show remarkable inhibition reaction against liver injuries in experimental liver injury models, and have completed the present invention.
An object of the present invention is to provide an N-substituted amide derivative represented by the formula ##STR2## wherein A is --CH(OH)-- or --C(.dbd.O)--, R.sup.1 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and R.sup.2 is an alkyl group having 1 to 6 carbon atoms.
In the present invention, the alkyl group may be straight or branched chained alkyl group such as, for example, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a n-hexyl group and the like.
Examples of typical compound of the present invention are N-(3,4-methylenedioxyphenacyl)acetamide, N-methyl-N-(3,4-methylenedioxyphenacyl)-n-hexanamide, N-(3,4-methylenedioxyphenacyl)-n-butanamide, N-(3,4-methylenedioxyphenacyl)-n-hexanamide and N-methyl-N-(.beta.-hydroxy-3,4-methylenedioxyphenethyl)acetamide.
The compounds of the present invention can be prepared, for example, by the processes showing by the following reaction schemes (wherein R.sup.1 and R.sup.2 are as defined above, and X and X' are each a halogen atom). ##STR3## Process 1: An amine of Formula II is reacted with an acid halide of Formula III in an organic solvent to give an amide derivative of Formula IV. Examples of the organic solvent used in the reaction are halogenated hydrocarbon such as chloroform and dichloromethane, and ethers such as ethyl ether, dioxane and tetrahydrofuran. The reaction temperature is from -10.degree. C. to the boiling point of the solvent, and preferably from 0.degree. C. to room temperature. The reaction can be thoroughly finished in about an hour.
Then, the compound of Formula IV is reacted with a dihalomethane in an organic solvent or without solvent in the presence of a base to give the compound of Formula V of the present invention. The dihalomethane may be dichloromethane, dibromomethane and the like. Examples of the organic solvent used are N,N-dimethylformamide, dimethyl sulfoxide and the like. The reaction temperature is from room temperature to the boiling point of the solvent. The reaction time can be recognized by observing the disappearance of the material by means of silica gel thin layer chromatography and the like.
Process 2: An .alpha.-halogenoacetophenone compound of Formula VI is reacted with an amine of Formula VII in a solvent to give an amino derivative of Formula VIII. Examples of the solvent used in the reaction are alcohols such as methanol and ethanol; ethers such as ethyl ether, dioxane and tetrahydrofuran; acetone, benzene, water and the like. The reaction temperature is from -10.degree. C. to the boiling point of the solvent, and preferably from 0.degree. C. to room temperature. The reaction is momentarily finished, but it may be carried out with stirring for 0.5 to 2 hours.
Then, the resulting amino derivative of Formula VIII can be converted to the compound of Formula V of the present invention by an ordinary acylation. Examples of the ordinary acylation are those carried out using acylating agents such as acid anhydrides (e.g., acetic anhydride, propionic anhydride, butyric anhydride and the like) in the presence of a base; those carried out using acylating agents such as acid halides (e.g., acetyl chloride, propionyl bromide, hexanoyl chloride and the like); those carried out by condensing with ethyl acetate, ethyl propionate, methyl butyrate and the like; and those carried out by condensing with carbonic acid derivatives such as acetic acid, propionic acid, butyric acid and the like in the presence of a condensing agent (e.g., dicyclohexylcarbodiimide, diethyl azodicarboxylate and the like). The reaction may be carried out by using a solvent such as, for example, pyridine, N,N-dimethylformamide, dimethyl sulfoxide, ethyl ether, benzene, toluene, water and the like. Examples of the base used in the reaction are sodium carbonate, potassium carbonate, sodium hydrogen carbonate, sodium hydroxide, pyridine, triethylamine and the like. The reaction temperature and reaction time are the same as those of an ordinary acylation.
Process 3: The .alpha.-halogenoacetophenone compound of Formula VI is reacted with hexamethylenetetramine in a solvent to give a quaternary ammonium salt of formula IX. The solvents used in this reaction are preferably halogenated hydrocarbons such as chloroform, dichloromethane and the like.
Then, the quaternary ammonium salt of Formula IX is decomposed by adding a mineral acid such as hydrochloric acid in an alcohol such as methanol and ethanol to give a primary ammonium salt, which is then subjected to an acylation similar to that of Process 2 to give a compound of Formula V wherein R.sup.1 is a hydrogen atom of the present invention.
Process 4: A compound of Formula I wherein A is --CH(OH)-- of the present invention can be prepared by a reduction of the compound of Formula V of the present invention obtained above with sodium borohydride in a solvent. The solvents used in this reaction are preferably alcohols such as methanol and ethanol, and ethers such as ethyl ether and tetrahydrofuran.
The compounds of the present invention inhibit serum GPT activity remarkably in experimental liver injury models, and therefore have an excellent inhibition effect on liver injuries. Accordingly, the compounds of the present invention are useful as prevention or therapeutic agents of liver injuries such as chronic hepatitis and hepatic cirrhosis. For the purposes, these compounds can be administered by oral route or by parenteral route such as intravenous, intramuscular, subcutaneous and percutaneous route. The dosage form of oral administration are tablets, capsules, granules, pills and the like, all of which may be prepared by known methods. For example, granules may be prepared using mannitol and corn starch as fillers, and hydroxypropylcellulose as a binder; and tablets may be prepared using crystalline cellulose and lactose as fillers, carboxymethylcellulose calcium as a disintegrator, polyvinylpyrrolidone as a binder and magnesium stearate as a lubricant. The dosage forms of parenteral administration are injectional preparations, ointments and the like, all of which may be prepared by ordinary manners.
The dose of the compound of the present invention depends on the compounds, administration route and severity of diseases, but usually it is in the range from 0.5 to 10 mg/kg/day.